1. Field of the Invention
This invention relates to a method for the optical resolution of a (.+-.)-2-(3-benzoyl)-phenylpropionic acid [namely a racemate].
The (.+-.)-2-(3-benzoyl)-phenylpropionic acid possesses an anti-inflammatory activity and an analgesic-antipyretic activity and finds utility as a medicine called as "ketoprofen."
2. Description of the Prior Art
As respects the physiological activity of this optically active compound, it has been known that the (+)-2-(3-benzoyl)phenylpropionic acid is more active than the (-)-2-(3-benzoyl)phenylpropionic acid [Farumashia, Vol. 11, No. 7, page 517, 1975] and, unlike other profenes which, in the human body, easily allow isomerization of their inefficaceous R forms [(-) forms] into their efficaceous S forms [(+) forms], the 2-(3-benzoyl)-phenylpropionic acid is difficult to isomere in this kind [R. T. Foster et al., J. Pharm. Sci., 77, 70-73 (1988)]. There has been expressed a desire for a practical method for the production of an optically active 2-(3-benzoyl)-phenylpropionic acid, particularly (+)-2-(3-benzoyl)-phenylpropionic acid.
As a means for producing an optically active 2-(3-benzoyl)phenylpropionic acid, a method which comprises causing (.+-.)-2-(3-benzoyl)-phenylpropionic acid to react with optically active 1-phenylethyl amine thereby synthesizing an amide, separating a diastereomer from the amide by liquid chromatography using silica gel, and oxidatively hydrolyzing the diastereomer with nitrogen dioxide (N.sub.2 O.sub.4) [N. Blazevic et al., Acta Pharm. Jugoslav., 25, 155, (1975)] has been known to the art.
This method, however, does not deserve to be called a commercially feasible approach because it suffers from various disadvantages that the synthesis of the amide necessitates expensive dicyclohexyl carbodimide, that the separation of the diastereomer requires column chromatography and, moreover, the separation itself is attained only with difficulty, that the inevitable oxidative hydrolysis of the diastereomer requires the nitrogen dioxide and entails partial racemization, and that the 1-phenylethyl amine is deprived of optical activity in the course of the hydrolysis and, therefore, cannot be used again.
It, further, has a drawback that reuse of unnecessary diastereomer is not easy to attain.
The high-performance liquid chromatographic method known as a method of analysis directed to optical purity may be utilized for optical resolution. It does not fit mass production because it necessitates an expensive carrier [Oi et al, Bunseki Kagaku, Vol. 35, page 312, 1986 and B. Sallustio et al., J. Chromatogr., 374, 329. (1986)].
The present inventors have made a diligent study on the problem on the optical resolution of (.+-.)-2-(3-benzoyl)-phenylpropionic acid mentioned above and have consequently perfected the present invention.